Health Outcomes Associated with Olive Oil Intake: An Umbrella Review of Meta-Analyses

Several studies suggested a negative association between olive oil (OO) consumption and the risk of several chronic diseases. However, an attempt to systematically search, organize, and evaluate the existing evidence on all health outcomes associated with OO consumption is lacking. The objective of this review is to describe the multiple health outcomes associated with OO consumption. The Medline, Scopus, and Web of Science databases were searched through 5 April 2024. The selected studies met all of the following criteria: (1) a meta-analysis of both observational (case–control and cohort studies) and interventional studies (trials), (2) an evaluation of the association between OO consumption, mortality, and/or the incidence of non-communicable/chronic degenerative diseases, and (3) a study population ≥18 years old. Two independent reviewers extracted the relevant data and assessed the risk of bias of individual studies. The PRISMA statement and guidelines for the Integration of Evidence from Multiple Meta-Analyses were followed. The literature search identified 723 articles. After selection, 31 articles were included in this umbrella review. The primary health benefits of OO were observed in cardiovascular diseases and risk factors, cancer, mortality, diabetes, and specific biomarkers related to anthropometric status and inflammation. As a key component of the Mediterranean diet, OO can be considered a healthy dietary choice for improving positive health outcomes.


Introduction
Olive oil is obtained from the fruit of the olive tree (Olea europaea L.), exclusively by mechanical and physical means under certain conditions, particularly thermal conditions, that do not result in alterations in the oil, which has not undergone any treatment other than washing, decantation, centrifugation, and filtration [1].Olive oil is an important element of the Mediterranean diet, distinguished as a Cultural Heritage of Humanity by UNESCO in 2010 [2]; in fact, olive oil represents the main source of meal fat [3].
Epidemiologic evidence has consistently shown that an increased consumption of olive oil is associated with a reduced risk of various chronic diseases.The findings from several key studies illustrate the broad health benefits of olive oil, highlighted particularly in relation to cardiovascular disease, cancer, type 2 diabetes, body composition, blood pressure, inflammation, endothelial function, and hemostasis [4][5][6][7][8][9][10].The largest trial on the Mediterranean diet tested supplementation with extra virgin olive oil in one arm and reported a significant reduction in hard endpoint compared to the control group [11].
Regarding the biochemical mechanisms through which olive oil components may exert their effects, some in vitro and animal studies have described the action on inflammation mediators, lipoprotein metabolism, endothelial function, and cell cycle regulation and metabolism [20][21][22][23][24][25][26].
Despite the nutritional and epidemiological studies cited, many questions about the role of olive oil in disease remain unanswered; moreover, causality is difficult to prove.Previous efforts to systematically appraise the evidence on olive oil have focused on single disease endpoints (e.g., CVD).Instead, in this review, we used the umbrella review methodology (i.e., the syntheses of existing systematic reviews with meta-analyses) [27][28][29] to capture the full spectrum of outcomes associated with olive oil intake and to systematically assess the quality and strength of the evidence across all health outcomes and medical conditions to highlight those with the strongest evidence.

Materials and Methods
The protocol of the current umbrella review was registered in the PROSPERO International Prospective Register of Systematic Reviews database (ID number: 42023450410, www.crd.york.ac.uk/PROSPERO (accessed on 14 August 2023)).This study was carried out according to the recommendations of the "Preferred Reporting Items for Systematic reviews and Meta-Analyses" (PRISMA) checklist [27].
The aim of this general review was to provide health decision-makers with information on a broad topic involving multiple outcomes.The specific questions included the following: "Is olive oil consumption beneficial for population health?Is the existing evidence strong and valid enough to assess the association between olive oil intake and health outcomes in adults?"

Search Strategy and Data Sources
Two authors (RF and MC) independently conducted a systematic literature search until 5 April 2024, without restriction, through three electronic databases: PubMed, http: //www.ncbi.nlm.nih.gov/pubmed/(accessed on 5 April 2024); Web of Science, http:// wokinfo.com/(accessed on 5 April 2024); and Scopus, https://www.scopus.com/(accessed on 5 April 2024) using the keywords "olive oil" AND "meta-analysis" in the title or abstract.Furthermore, the reference lists of the included articles were manually examined to find additional relevant publications.In addition to an electronic search, the authors reviewed the references quoted in the full-text articles to intercept further interesting articles.We included meta-analyses of observational and intervention studies investigating olive oil as a possible determinant for any health outcome.

Selection Process
The list of selected studies, the removal of duplicates, and the selection of studies of interest were managed with Zotero.Two authors (RF and MC) independently screened the titles and abstracts of all remaining articles before assessing the full texts.A third reviewer (PR) solved any disagreements.We used the PICOS framework (Population/Intervention/Comparison/Outcome/Study design) to guide our selection criteria.We included studies that met the following inclusion criteria: (a) an evaluation of the association between olive oil intake, mortality, and/or the incidence of non-communicable/chronic degenerative diseases; (b) adults aged 18 years or over in order to avoid the influence of exposure time on the outcome assessed; (c) a healthy or unhealthy population; (d) a reported summary of the estimated effect size, such as odds ratios (ORs), hazard ratios (HRs), or risk ratios (RRs), and their corresponding 95% confident intervals (CIs) for observational studies; and (e) reported effects such as weighted or standardized mean differences with confidence intervals (95%) for intervention trials.We excluded studies (a) published in a language other than English; (b) on animal models; (c) without a defined control group or a defined comparator.We also excluded meta-analysis with oleic acid or olive oil phenols as single components instead of olive oil.

Data Extraction
Using a previously defined form, the authors independently extracted data (RF and PR from observational studies, MC and IG from intervention studies).Any disagreements were resolved through discussion.From each meta-analysis, data extracted included the first author's last name, year of publication, type of outcomes (cancer or non-cancer), number and design of included studies, comparison criteria, study population characteristics, number of events, sample size, type of reported effect size (e.g., relative risk/hazard ratio, odds ratio, mean difference), corresponding 95% CI, tools used to assess risk of bias and heterogenicity.Data were grouped according to the type of outcome.

Quality Assessment
The methodological quality of the included meta-analyses was independently assessed by two authors (RF and PR).In the event of a disagreement, a third investigator (either MC or IG) was involved.We evaluated the methodological quality of the included metaanalysis using the "A Measurement Tool to Assess systematic Reviews 2" (AMSTAR-2) questionnaire, which comprises 16 items.The overall assessment focused on deficiencies in the following seven critical areas: the protocol was defined before starting the study (study registration) (item 2); an exhaustive literature search was conducted (item 4); the rationale for the exclusion of individual studies was discussed (item 7); an appropriate method was used to analyze the risk of bias of individual studies (item 9); appropriate methods were used for the statistical combination of results (item 11); possible bias was considered in the discussion of results (item 13); the possible impact of publication bias was considered (item 15).
The overall confidence level ranged from high (no or one non-critical weakness), to moderate (more than one non-critical weakness), low (one critical weakness), and critically low (more than one critical weakness) [30].

Data Analysis
For each meta-analysis, we presented the most adjusted estimated summary effect size with their 95% CI using random or fixed effects models.Dose-response analyses were also extracted from each study.Publication bias was assessed by the Egger regression asymmetry test [31].The heterogeneity among studies was assessed by the I 2 metric and Cochran's Q test.For heterogeneity and publication bias, as also for other tests, p < 0.05 was adopted for the significance threshold because of the limited statistical power.

Quality Assessment of the Meta-Analyses Included
Using the AMSTAR 2 questionnaire, we assessed the methodological quality of the meta-analyses included in this umbrella review.The quality judgement was rated high in four articles, moderate in six articles, low in two, and critically low in twenty.The main criticisms were often related to the absence of PICO components in the research question and inclusion criteria, inadequate search strategies for literature, an insufficient discussion of the potential impact of heterogenicity, and bias on the results.Additionally, the sources of funding for the studies included in the review were omitted.The overall judgment is reported in Tables 1 and 2, whereas the item-by-item assessment for each included meta-analysis is detailed in Supplementary Table S1.
All studies assessing the association between CVD and olive oil consumption found a significant association [4,61,[67][68][69][70].Concerning CHD, all referenced articles reported a significant association [4,61,69,70] with olive oil consumption.The association between stroke and olive oil consumption was significant in all the articles that examined this outcome [4,61,69,70], except in the study by Ke 2024, which compared the highest versus the lowest consumption levels [61].

Pressure Ulcers
A single meta-analysis assessed the association between pressure ulcers and olive oil [71].This high quality meta-analysis highlighted a reduced incidence of pressure ulcers following topical application of EVOO, with no adverse effect observed (Table 1).

Mortality
Five articles evaluated the association between all causes of mortality and olive oil [4,61,67,69,72], two addressed cardiovascular mortality and olive oil [61,69], and one discussed cancer mortality and olive oil [61] (Table 1).The number of studies included varied from four [72] to fourteen [61].The population examined in all the studies consisted of mixed males and females over 18 years old [4,61,67,69,72].
Olive oil appears to have a significant protective effect on all-cause mortality in all but one study [72].Similarly, a significant association between cardiovascular mortality and olive oil consumption was found in one study [61], but not in another [69].No significant preventive effect was observed for cancer mortality and olive oil [4,61].
The quality was low for one study [61], critically low for three studies [67,69,72], and high for the study of Martinez-Gonzales 2022 [4].
For further information, see Table 1.

Antropometric Indices
Four meta-analysis [47][48][49]54] explored the association between olive oil and various anthropometric indices, including Body Mass Index (BMI) [47][48][49], Waist Circumference (WC) [47][48][49], Hip Circumference (Hip C) [49], WC/Hip C [47,49], Weight [47], Total Body Fat [49], muscle mass [49], and body composition [54].The meta-analysis considered olive oil or EVOO or refined olive oil administered in various forms, either as a culinary ingredient (consumed after cooking or crude) or in capsules.Comparisons varied widely, ranging from a low-fat diet and other vegetable oils [48], to a regular diet with other vegetable oils or animal fats [47] and diets that were either standard, hypocaloric, or supplemented with nuts or PUFAs or a low-fat diet [49,54].All of the studies were performed on a population over 18 years old, composed of men and women.One study enrolled only unhealthy subjects [48], and one both healthy and unhealthy subjects [54].We found no significant differences in anthropometric indices between intervention and control groups.Only BMI was significantly lower in the population that consumed olive oil than in a population exposed to a low-fat diet and other oils [48].
The analysis of the quality of the studies shows moderate quality in three studies [47][48][49] and critically low quality in one [54].

Inflammatory Biomarkers
Three meta-analysis evaluated the relationship between olive oil consumption and inflammatory biomarkers [9,14,47], focusing on CRP [48,57,65], IL-6 [48,57,65], IL-10 [47], TNF-α [9,47], flow-mediated dilatation, Adiponectin, sE-Selectin, sP-Selectin, sICAM-1, and sVCAM-1 [9].All three studies incorporated EVOO or olive oil as a culinary ingredient of the diet, and additionally, one study also explored the effects of olive oil administered in capsules [9].Comparisons varied widely, ranging from a regular diet with other oils or butter [47], to a low-fat diet or a diet enriched with nuts and PUFAs, or other vegetable and animals oils, or a general healthy diet [9], to diets rich in saturated fatty acids or other oil [14].The numbers of studies included in the metanalyses ranged from three to fourteen.The study populations were all over 18 years of age, and included both women and men, healthy and unhealthy in two studies [9,14,47].A significant reduction in IL-6 was observed in the intervention groups in two of the three meta-analyses [9,14].Similarly, a negative trend for CRP was noted among EVOO consumers, although this was significant in one study [9].One article identifieda positive association for flow-mediated dilatation, adiponectin, TNFα, sE-Selectin, sP-Selectin, sICAM-1, and sVCAM-1 [9], although significance was only achieved for flow-mediated dilatation and sE-Selectin.Two of the articles were rated as moderate in quality [14,47], while one was rated as critically low [9].

Discussion
Our findings suggest that olive oil intake generally plays a preventive role against cancer risk, particularly significant when analyses combine both case-control and cohort study designs, or when only case-control studies are considered.On the other hand, when synthesizing results solely from cohort studies, a reduction in cancer risk was generally observed, but this lacks statistical significance.Similarly, the preventive effect of olive oil on cancer mortality, based on prospective studies, was found to be at the limit of statistical significance [61].One reason for these marginal findings could be the limited number of cohort studies linking olive oil intake to cancer risk and mortality.Indeed, the most recent meta-analysis by Ke et al. in 2024 included merely seven and six cohort studies regarding tumor incidence and mortality, respectively [61].Moreover, it is problematic that risk values associated with various organ-specific tumors (breast, skin, lung, bladder, and colon) are aggregated, as these organs likely vary in their sensitivity to olive oil's preventive effects.Furthermore, most cohort studies only considered olive oils as part of the broader Mediterranean diet, without distinguishing the type of olive oil consumed.The potential cancer-preventive properties of olive oil are supported by numerous in vitro and in vivo studies, highlighting the role of its unique components, such as oleic acid and squalene; however, phenolic compounds, including simple phenols, secoiridoids, and lignans, have garnered the most attention for their substantial bioactive properties [73].In vitro studies on tumor cells have clearly shown that these compounds can inhibit all stages of the carcinogenesis process (initiation, promotion, and progression) [74].Animal carcinogenesis model studies have further demonstrated the anti-carcinogenic effects of both olive oil and its phenolic compounds [75].It is important to note the significant variability in phenolic content across different olive oils [76], ranging from nearly zero in common refined olive oils, to 800 mg/Kg in extra virgin olive oils [76].Unfortunately, no existing epidemiological studies have considered the phenolic content of the olive oil consumed in association with the risk of cancer.Further prospective studies, precisely calibrated to the type of olive oil consumed, are essential to determine if virgin olive oil may have a cancer-preventive activity.
A recent umbrella review [41] found that a Mediterranean diet and high olive oil consumption significantly reduces stroke risk, but does not significantly affect CHD risk.Moreover, three recent meta-analyses [4,61,67] confirmed the protective role of OO in CVD and stroke and also observed benefits of olive oil for CHD.
Analyzing only high-quality articles (AMSTAR: High, Moderate) that investigated cardiovascular risk factors, such as high blood glucose levels, hypertension, and dyslipidemia, we observed substantial variability in the association of OO and the outcomes.For instance, one study highlighted the beneficial effect of high-phenol OO compared with low-phenol OO on ox-LDL levels and SBP [60], while another found that EVOO intake has a significant impact on insulin level [47]; finally, a third study [48] showed a trivial effect of OO consumption vs. LFD/other oil on serum lipid level and glycemic profile.Results about the importance of the kind of OO used are controversial.
Overweight and obesity are significant risk factors for CVD [77].Diet composition has a great impact on body composition.The Mediterranean diet, with EVOO as a typical fat source, is often recommended as a strategy to reduce body fat.However, the impact of EVOO on anthropometric indices remains clear.This umbrella review included four meta-analyses on the association between olive oil intake and various anthropometric parameters, including BMI, WC, WC/hip ratio, body fat, weight, and muscle mass, have been considered.The results are often contradictory; only the BMI appears to decrease significantly in olive oil intervention groups compared to controls.This inconsistency may stem from the heterogeneity of the subjects involved (healthy or not), the type of olive oil used (refined, EVOO, whether cooked or raw, in capsules), and the duration of the intervention.Moreover, the specific olive cultivar used can significantly influence the concentration and effects of bioactive molecules [78].
It is well known that chronic inflammation plays a crucial role in the upset of CVDs, which are considered inflammatory diseases [79].There is substantial evidence of the antiinflammatory properties of the Mediterranean diet [80].It is therefore very interesting to evaluate the association between olive oil intake and inflammatory biomarkers.Although the oldest meta-analysis [9] showed a statistically significant reduction in CRP and IL-6 levels in subjects treated with olive oil, more recent meta-analyses [14,47] have not confirmed these findings.However, it should be noted that the older meta-analysis included a much larger sample size (3701) than the more recent ones (485 and 493).In addition, it is possible that, as noted with anthropometric measures, various variables in intervention trials can affect outcomes.
Our results corroborate findings from the study of Toi et al. [40] on the preventive role of OO against type 2 diabetes mellitus (T2DM).The intake of OO appears beneficial for the prevention and management of this disease and it should be promoted at both individual and population levels to mitigate the future burden of T2DM.
Among the outcomes considered in this umbrella review, we found the result of the meta-analysis on pressure ulcers (PUs) of particular interest [71].Despite including only four RCTs, the analysis indicated that topical application of olive oil reduces the incidence of PUs by both extending the time of development and reducing days of hospitalization.This finding complements the benefits of EVOO on wound healing [81].Because of its affordability, olive oil can represent a frequently used option for this injury.

Strengths and Limitations
Umbrella reviews, which analyze the overall results of previously published metaanalyses, represent a valuable tool for defining evidence-based public health choices; however, they may contain some limitations.Specifically, in this case, (i) according to AMSTAR-2, only three publications of the thirty-one selected publications are of high quality, while twenty publications (approximately 65%) are of critically low quality; (ii) studies on the effect of foods or nutrients are challenging to interpret due to variability in the methods used to quantify intake and the presence of different diets followed by the recruited populations; (iii) it must also be considered that the chemical composition of olive oil can vary significantly based on the cultivar, the degree of ripeness of the olives at harvest, and the pressing technique used [78], factors that alter the concentration and type of polyphenols, bioactive compounds crucial to the health effects of olive oil [82].
The results highlighted by this umbrella review underline the need to carry out further intervention trials using a common protocol in terms of time of intervention, type of olive oil used, characteristics of the population, and comparator, especially when results are expressed as MD.

Conclusions
The evidence synthesized in this umbrella review underscores the multifaceted health benefits associated with olive oil consumption, emphasizing its role in reducing the risk of chronic diseases such as cancer, cardiovascular diseases, and type 2 diabetes.However, significant heterogeneity exists among studies, particularly regarding the types of olive oil used, the methods of administration, and population characteristics.The preventive potential of olive oil against cancer is supported by both in vitro and in vivo studies, highlighting the importance of its phenolic compounds.The evidence suggests a preventive activity in most cancer types, including breast cancer and digestive system cancers.
The health-promoting effects of olive oil result from a plethora of bioactive compounds such as monounsaturated fats, phenolic compounds, polyphenols, and vitamins that, by their anti-inflammatory and antioxidant properties [83], their epigenetic modification ability [84], and their microbiota regulation [85], contribute to the prevention of different chronic degenerative diseases.
However, the absence of epidemiological studies that consider the phenolic concentration of olive oil necessitates further research to ascertain the specific effects of various olive oil types on cancer prevention.The review also highlights the protective role of olive oil in cardiovascular health.Significant associations were found between olive oil consumption and reduced risk of stroke and cardiovascular disease, though results for coronary heart disease remain inconsistent.Notably, the mode of olive oil administration appears to influence health outcomes, with liquid oil showing benefits for blood pressure regulation, unlike capsule forms.Concerning diabetes, our findings confirm that olive oil intake could be advantageous for the prevention and management of type 2 diabetes.This is supported by evidence showing a significant impact of olive oil on glucose homeostasis and insulin sensitivity, suggesting its promotion at both individual and population levels to mitigate the burden of type 2 diabetes.The impact of olive oil on anthropometric indices and inflammatory biomarkers remains inconclusive, likely due to variability in study designs, populations, and olive oil types.While some studies report beneficial effects on BMI and inflammatory markers, others do not, pointing to the need for standardized intervention protocols in future research.
In summary, while olive oil exhibits considerable potential in promoting health and preventing disease, consistent methodological approaches in future trials are essential to validate these findings and clarify the specific conditions under which olive oil can be most beneficial.

Figure 1 .
Figure 1.PRISMA flow chart of study selection.

Figure 1 .
Figure 1.PRISMA flow chart of study selection.

Table 1 .
Characteristics of studies that consider outcomes described with risk.

Table 2 .
Characteristics of studies that consider outcomes described with MD.